Primary sclerosing cholangitis (PSC) is a progressive liver disease strongly associated with inflammatory bowel disease (IBD). About 75% of PSC patients are diagnosed with IBD, most commonly ulcerative colitis (UC) and conversely, 5-7% of IBD patients develop PSC. Life expectancy of PSC patients is reduced due to lack of medical therapy, advancement to end-stage liver disease and an increased risk of colon cancer and cholangiocarcinoma (CCA). Thus, while rare in the population, PSC is a notable threat to patients with IBD. Like IBD, PSC is thought to arise as the result of interacting genetic and environmental risk factors. Taken further, the IBD-PSC relationship may be one of overlapping risk capable of prompting both liver and gut involvement, with distinct mechanisms further influencing organ specific disease development. Yet, comprehensive studies focused on the dissection of the genetic and environmental risks in PSC, and its relationship with UC, have not been performed. To this end, we created the PSC Resource of Genetic Risk, Environment and Synergy Studies (PROGRESS). This resource currently comprises 618 PSC patients and 779 primary clinic-based controls; the largest of its kind in North America. Moreover, we have established collaborations between PROGRESS and the Norwegian PSC Research Center (NOPSC), UK PSC Consortium (UKPSC) and IBD Genetics Consortium (IBDGC) to share resources in pursuit of our common goals. In this application, we propose to test the hypothesis that genetic variants and/or environmental mediators contribute to PSC susceptibility and its association with UC. To achieve this, we propose three Specific Aims. In Aim 1, we will expand PROGRESS through continued recruitment of PSC patients at Mayo Clinic and seven other participating medical centers across North America. In Aim 2, we will perform 2 genome wide association studies (GWAS) to identify genetic variants for: (a) susceptibility to PSC- discovery study: 2000 PSC patients and 5000 controls; replication study: 1900 PSC patients and 3000 controls; and, (b) susceptibility to PSC in UC- discovery study: 1400 PSC patients with UC and 1000 UC patients without PSC; replication group: 1330 PSC patients with UC and 1000 UC patients without PSC. In Aim 3, we will determine environmental risk factors for PSC using validated, self-administered questionnaires collected from PROGRESS participants (1000 PSC patients and 1000 controls). This study will begin to identify the genetic variants and environmental factors associated with PSC and its relationship with UC. These findings will serve as foundation for future risk assessment and disease prevention strategies as well as for basic research studies looking for implicated mechanisms and potentially leading to novel therapies for PSC.